Polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid and uses thereof

ABSTRACT

Crystalline polymorph forms of 2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid are described. Pharmaceutical compositions and the uses of such compounds, compound forms, and compositions for the treatment of a variety of diseases and conditions are also presented.

CROSS-REFERENCE

This application claims priority to U.S. Provisional Application No.61/428,660, filed Dec. 30, 2010, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

Described herein are polymorphic forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, which is known to decrease uric acid levels.

BACKGROUND OF THE INVENTION

Gout is associated with elevated levels of uric acid that crystallizeand deposit in joints, tendons, and surrounding tissues. Gout is markedby recurrent attacks of red, tender, hot, and/or swollen joints.

SUMMARY OF THE INVENTION

Described herein are crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid:

In one aspect described herein are crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid characterized bypeaks at 10.32, 18.84 and 20.75°2θ±0.1°2θ. In further embodiments, sucha crystalline polymorph is further characterized by at least two furtherpeaks at 6.80, 21.54, 24.97, 25.53, 27.28 and 27.60°2θ±0.1° 2θ. In yetfurther embodiments, the crystalline polymorph exhibits an x-ray powderdiffraction pattern substantially the same as the x-ray powderdiffraction pattern shown in FIG. 1. In yet further embodiments, thecrystalline polymorph exhibits an x-ray powder diffraction patternsubstantially the same as the x-ray powder diffraction pattern shown inFIG. 2. In a related aspect described herein are crystalline polymorphsof2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, characterized by an endothermic point onset at about 151° C., asdetermined by differential scanning calorimetry. In a furtherembodiment, the crystalline polymorph is characterized by a differentialscanning calorimetry pattern substantially the same as the differentialscanning calorimetry pattern shown in FIG. 3. In another related aspectdescribed herein is the crystalline polymorph form 1 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. Also describedherein are crystalline polymorphic forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid made by a method comprising the step of crystallizing amorphous2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid from a mixture of water and acetic acid. In a related aspectdescribed herein, are solid pharmaceutical compositions comprising aneffective amount of the crystalline polymorph characterized by theaforementioned diffraction patterns, an effective amount of thecrystalline polymorph characterized by the aforementioned differentialscanning calorimetry patterns, or an effective amount of the crystallinepolymorph form 1, as an active ingredient; and at least one excipient orcarrier. Also described herein are methods for treating or preventinghyperuricemia or a disease caused by elevated uric acid levels,comprising administering an effective amount of the crystallinepolymorph characterized by the aforementioned diffraction patterns, aneffective amount of the crystalline polymorph characterized by theaforementioned differential scanning calorimetry patterns, or aneffective amount of the crystalline polymorph form 1. Also describedherein are methods for treating or preventing gout, comprisingadministering an effective amount of the crystalline polymorphcharacterized by the aforementioned diffraction patterns, an effectiveamount of the crystalline polymorph characterized by the aforementioneddifferential scanning calorimetry patterns, or an effective amount ofthe crystalline polymorph form 1.

In another aspect, described herein are crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid characterized by peaks at 10.46, 18.76, and 19.83°2θ±0.1°2θ. Infurther embodiments, such a crystalline polymorph is furthercharacterized by at least one further peak at 18.21 or 23.08°2θ±0.1° 2θ.In yet further embodiments, the crystalline polymorph exhibits an x-raypowder diffraction pattern substantially the same as the x-ray powderdiffraction pattern shown in FIG. 5. In yet further embodiments, thecrystalline polymorph exhibits an x-ray powder diffraction patternsubstantially the same as the x-ray powder diffraction pattern shown inFIG. 6. In a related aspect described herein are crystalline polymorphsof 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid, characterized byan endothermic point onset at about 175° C., as determined bydifferential scanning calorimetry. In a further embodiment, thecrystalline polymorph is characterized by a differential scanningcalorimetry pattern substantially the same as the differential scanningcalorimetry pattern shown in FIG. 8. In another related aspect describedherein is the crystalline polymorph form 2 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. Also describedherein are crystalline polymorphic forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid made by a method comprising the step of crystallizing amorphous2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid from a mixture of water and ethyl acetate. In a related aspectdescribed herein are solid pharmaceutical compositions comprising aneffective amount of the crystalline polymorph characterized by theaforementioned diffraction patterns, an effective amount of thecrystalline polymorph characterized by the aforementioned differentialscanning calorimetry patterns, or an effective amount of the crystallinepolymorph form 2, as an active ingredient; and at least one excipient orcarrier. Also described herein are methods for treating or preventinghyperuricemia or a disease caused by elevated uric acid levels,comprising administering an effective amount of the crystallinepolymorph characterized by the aforementioned diffraction patterns, aneffective amount of the crystalline polymorph characterized by theaforementioned differential scanning calorimetry patterns, or aneffective amount of the crystalline polymorph form 2. Also describedherein are methods for treating or preventing gout, comprisingadministering an effective amount of the crystalline polymorphcharacterized by the aforementioned diffraction patterns, an effectiveamount of the crystalline polymorph characterized by the aforementioneddifferential scanning calorimetery patterns, or an effective amount ofthe crystalline polymorph form 2.

In a further aspect are solid pharmaceutical compositions comprising aneffective amount of at least two of the aforementioned crystallinepolymorph forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid; and at least oneexcipient or carrier.

In a further aspect are methods for treating or preventing hyperuricemiaor a disease caused by elevated uric acid levels, comprisingadministering an effective amount of at least two of the aforementionedcrystalline polymorph forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid; and at least one excipient or carrier.

In a yet further aspect are methods for treating or preventing gout,comprising administering an effective amount of at least two of theaforementioned crystalline polymorph forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid; and at least one excipient or carrier.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 represents an illustrative X-ray Powder Diffraction Pattern ofPolymorph form 1 (Raw Data).

FIG. 2 represents an illustrative X-ray Powder Diffraction Pattern ofPolymorph form 1 (Background Subtracted and Kα2 Stripped).

FIG. 3 represents an illustrative Differential Scanning calorimetrypattern of Polymorph form 1.

FIG. 4 represents illustrative Thermogravimetric Analyses (a) Rep 1 and(b) Rep 2 of Polymorph form 1.

FIG. 5 represents an illustrative X-ray Powder Diffraction Pattern ofPolymorph form 2 (Raw Data).

FIG. 6 represents an illustrative X-ray Powder Diffraction Pattern ofPolymorph form (Background Subtracted and Kα2 Stripped).

FIG. 7 represents an illustrative overlay of X-ray Powder DiffractionPatterns of Polymorph form 1 (lower) and form 2 (upper).

FIG. 8 represents an illustrative Differential Scanning calorimetrypattern of Polymorph form 2.

FIG. 9 represents an illustrative ¹H NMR (DMSO-d₆) spectrum of Polymorphform 2.

FIG. 10 represents an illustrative HPLC trace of Polymorph form 2.

FIG. 11 represents an illustrative Thermogravimetric Analysis trace ofPolymorph form 2.

FIG. 12 represents an illustrative Gravimetric Vapor Sorption study ofPolymorph form 1 and 2.

DETAILED DESCRIPTION OF THE INVENTION

While certain embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will occur to those skilled inthe art without departing from the invention. It should be understoodthat various alternatives to the embodiments described herein are, insome circumstances, employed in practicing the invention. It is intendedthat the following claims define the scope of the invention and thatmethods and structures within the scope of these claims and theirequivalents be covered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, without limitation, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

The present invention relates to polymorphic forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid, which is knownto decrease uric acid levels.

The term “polymorph form 1” refers to a crystalline form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid that exhibits anx-ray powder diffraction pattern substantially the same as that shown inFIG. 1, and/or FIG. 2 and/or a differential scanning calorimetry profilesubstantially the same as that shown in FIG. 3.

The term “polymorph form 2” refers to a crystalline form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid that exhibits anx-ray powder diffraction pattern substantially the same as that shown inFIG. 5, and/or FIG. 6 and/or a differential scanning calorimetry profilesubstantially the same as that shown in FIG. 8.

The present invention also relates to solid pharmaceutical compositions,comprising, as an active ingredient, an effective amount of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as the crystalline polymorph form 1, the crystalline polymorphform 2, or a combination thereof.

The present invention also relates to methods for treating or preventingdiseases, comprising administering an effective amount of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as the crystalline polymorph form 1, the crystalline polymorphform 2, or a combination thereof.

Also described are processes for the preparation of the crystallinepolymorph forms 1 and 2.

2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid

Described herein are polymorph forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid which is known to decrease uric acid levels.2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid and related compounds are described in US Patent ApplicationPublications 2008-0176850, US 2009-0197825, US 2010-0056464, US2010-0056465, US 2010-0069645, and US 2010-0081827.

Polymorph Form 1

In one embodiment,2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatepolymorph Form 1 exhibits an x-ray powder diffraction patterncharacterized by the diffraction pattern summarized in Table 1A or Table1B. In some embodiments, provided herein is a polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatecomprising at least 3 peaks of (±0.1°2θ) of Table 1A or 1B. In certainembodiments, provided herein is a polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatecomprising at least 4 peaks of (±0.1° 2θ) of Table 1A or 1B, at least 5peaks of (±0.1°2θ) of Table 1A or 1B, at least 6 peaks of (±0.1°2θ) ofTable 1A or 1B, at least 8 peaks of (±0.1°2θ) of Table 1A or 1B, atleast 10 peaks of (±0.1°2θ) of Table 1A, at least 15 peaks of (±0.1°2θ)of Table 1A, at least 20 peaks of (+0.1°2θ) of Table 1A, at least 25peaks of (±0.1°2θ) of Table 1A, or at least 30 peaks of (±0.1°2θ) ofTable 1A.

TABLE 1A form 1 °2θ d space (Å) Intensity (%) 10.32 8.562 100 18.844.706 32.7 20.75 4.277 23.2 27.28 3.266 13.6 27.60 3.229 11 21.54 4.12310.4 25.53 3.487 9.8 6.80 12.989 9.4 24.97 3.563 9.1 28.43 3.137 8.419.98 4.441 6.9 29.35 3.040 6.7 15.88 5.577 5.4 23.13 3.842 4.8 26.343.381 4.8 18.56 4.777 4.1

TABLE 1B form 1 ° 2θ d space (Å) Intensity (%) 10.32 8.562 100 18.844.706 32.7 20.75 4.277 23.2 27.28 3.266 13.6

In one embodiment provided herein, the polymorph form 1 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateis characterized by x-ray powder diffraction pattern peaks at 10.32,18.84, and 20.75 °2θ±0.1°2θ. In further embodiments, the polymorph form1 is further characterized by at least one peak appearing at 6.80,21.54, 24.97, 25.53, 27.28 and 27.60 °2θ±0.1°2θ. In further embodiments,the polymorph form 1 is further characterized by at least two peaksappearing at 6.80, 21.54, 24.97, 25.53, 27.28 and 27.60°2θ±0.1°2θ. Inyet still further embodiments, the polymorph exhibits an x-ray powderdiffraction pattern substantially the same as the x-ray powderdiffraction pattern shown in FIG. 1.

Polymorph Form 2

In one embodiment,2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatepolymorph Form 2 exhibits an x-ray powder diffraction patterncharacterized by the diffraction pattern summarized in Table 2A or Table2B. In some embodiments, provided herein is a polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatecomprising at least 3 peaks of (±0.1°2θ) of Table 2A or 2B. In certainembodiments, provided herein is a polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatecomprising at least 4 peaks of (±0.1°2θ) of Table 2A or 2B, at least 5peaks of (±0.1°2θ) of Table 2A or 2B, at least 6 peaks of (±0.1°2θ) ofTable 2A or 2B, at least 8 peaks of (±0.1°2θ) of Table 2A or 2B, atleast 10 peaks of (0.1°2θ) of Table 2A, at least 15 peaks of (±0.1° 2θ)of Table 2A, at least 20 peaks of (±0.1°2θ) of Table 2A, at least 25peaks of (±0.1°2θ) of Table 2A, or at least 30 peaks of (±0.1°2θ) ofTable 2A.

TABLE 2A form 2 Observed °2θ d space (Å) Intensity (%) 7.97 11.086 13.89.66 9.148 26.1 10.46 8.449 83.8 11.96 7.394 41.3 12.55 7.046 16.7 12.946.836 15.7 13.82 6.402 41.6 16.19 5.471 49.8 18.21 4.867 74.0 18.764.727 81.4 19.02 4.662 35.6 19.51 4.548 15.9 19.83 4.474 100.0 20.404.349 13.4 21.36 4.157 12.3 22.50 3.948 36.7 22.88 3.884 30.6 23.083.850 56.1 24.01 3.704 42.1 25.15 3.539 35.2 25.46 3.496 20.5 26.063.417 13.4 26.51 3.360 35.7 27.97 3.187 26.8 29.93 2.983 37.0 30.422.936 12.4 31.77 2.814 17.1 32.35 2.765 38.2 34.26 2.615 12.8 38.012.366 16.5 38.88 2.314 10.0

TABLE 2B form 2 Representative °2θ d space (Å) Intensity (%) 19.83 4.474100.0 10.46 8.449 83.8 18.76 4.727 81.4 18.21 4.867 74.0 23.08 3.85056.1

In one embodiment provided herein, the polymorph form 2 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateis characterized by x-ray powder diffraction pattern peaks at 10.46,18.76, and 19.83°2θ±0.1°2θ. In further embodiments, the polymorph form 2is further characterized by at least one peak appearing at 18.21, or23.08°2θ±0.1°2θ. In further embodiments, the polymorph form 2 is furthercharacterized by two peaks appearing at 18.21, or 23.08°2θ±0.1°2θ. Inyet still further embodiments, the polymorph form 2 exhibits an x-raypowder diffraction pattern substantially the same as the x-ray powderdiffraction pattern shown in FIG. 5.

In certain instances, the crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatewere found to exhibit increased stability in comparison to the amorphoussolid state form of the carboxylic acid. In some instances, improvedstability of the crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateprovides for the preparation of pharmaceutical dosage forms displayingreduced variability in the dosage present in a given dosage form,reduction in the presence of impurities in the final pharmaceuticalproduct, and an improved shelf life of formulated dosage forms whencompared to the pharmaceutical dosage form prepared with the amorphoussolid state form of the carboxylic acid. In some embodiments, apolymorph described herein (e.g., Form 1 or Form 2) demonstrates nodegradation (e.g., less than 0.01%, less than 0.1%, less than 0.5% bywt.) for at least 3 months under accelerated conditions (e.g., 40°C.-75% RH), for at least 4 months under accelerated conditions (e.g.,40° C.-75% RH), for at least 5 months under accelerated conditions(e.g., 40° C.-75% RH), for at least 6 months under acceleratedconditions (e.g., 40° C.-75% RH), for at least 9 months underaccelerated conditions (e.g., 40° C.-75% RH), for at least 12 monthsunder accelerated conditions (e.g., 40° C.-75% RH), and/or (ii) for atleast 12 months under long-term conditions (e.g., 25° C.-60% RH), for atleast 18 months under long-term conditions (e.g., 25° C.-60% RH), for atleast 24 months under long-term conditions (e.g., 25° C.-60% RH).

Additionally, in certain instances, the crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatewere found to exhibit decreased hygroscopicity compared to other solidstate forms as determined by gravimetric vapor sorption (GVS) studies.FIG. 12 illustrates a GVS study of form 1 and form 2. Form 1 was foundto adsorb<0.2% w/w at high humidity and Form 2 was found to adsorb<0.1%w/w at high humidity. This property of decreased hygroscopicity greatlyaids in the preparation of solid pharmaceutical dosage forms.

Admixture with Amorphous Solid State Forms

In certain embodiments, any of the polymorphs described herein (e.g.,Form 1) optionally comprises (or is intermixed or in combination with) acertain amount of amorphous2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate.In some embodiments, the amorphous component of the polymorph (e.g.,Form 1) or polymorph combination comprises less than 50 wt. % of thepolymorph or polymorph combination, less than 25 wt. % of the polymorphor polymorph combination, less than 15 wt. % of the polymorph orpolymorph combination, less than 10 wt. % of the polymorph or polymorphcombination, or less than 5 wt. % of the polymorph or polymorphcombination.

Particle Size

In certain embodiments, provided herein is a2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatepolymorph particle (e.g., crystalline, or comprising a crystallinecomponent). In some embodiments, provided herein is a2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatepolymorph (e.g., crystalline, or comprising a crystalline component)having a particle size of about 5-50 microns. In some embodiments, theaverage particle size is at least 10 microns, 15-50 microns, 15-35microns, 35-45 microns, 35-40 microns, about 40 microns, or the like. Insome embodiments, particles of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(e.g., crystalline, or comprising a crystalline component, such as apolymorph of Form 1) having an average diameter of greater than 5 or 10microns have improved stability parameters compared to smallerdiameters.

Uric acid is the result of the oxidation of xanthine. Disorders of uricacid metabolism include, but are not limited to, polycythemia, myeloidmetaplasia, gout, a recurrent gout attack, gouty arthritis,hyperuricaemia, hypertension, a cardiovascular disease, coronary heartdisease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidneydisease, kidney stones, kidney failure, joint inflammation, arthritis,urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.

DEFINITIONS

The term “subject”, as used herein in reference to individuals sufferingfrom a disorder, and the like, encompasses mammals and non-mammals. Inone embodiment of the methods and compositions provided herein, themammal is a human.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to an amountof at least one agent or compound being administered that is sufficientto treat or prevent the particular disease or condition. The result isthe reduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in a disease. An appropriate“effective” amount in any individual case is determined using techniquessuch as a dose escalation study.

The term “substantially the same as” as used herein, refers to a powderx-ray diffraction pattern or differential scanning calorimetry patternthat is non-identical to those depicted herein, but that falls withinthe limits of experimental error, when considered by one of ordinaryskill in the art.

Modulating URAT-1 Activity

Also described herein are methods of modulating URAT-1 activity bycontacting URAT-1 with an amount of a polymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to modulate the activity ofURAT-1. The term “modulate” refers to either inhibiting or activatingURAT-1 activity. In some embodiments are provided methods of inhibitingURAT-1 activity by contacting URAT-1 with an amount of a polymorphicform of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to inhibit the activity of URAT-1.In some embodiments are provided methods of inhibiting URAT-1 activityin a solution by contacting said solution with an amount of apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein sufficient to inhibit the activity of URAT-1in said solution. In some embodiments are provided methods of inhibitingURAT-1 activity in a cell by contacting said cell with an amount of apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to inhibit the activity of URAT-1in said cell. In some embodiments are provided methods of inhibitingURAT-1 activity in a tissue by contacting said tissue with an amount ofa polymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to inhibit the activity of URAT-1in said tissue. In some embodiments are provided methods of inhibitingURAT-1 activity in blood by contacting the blood with an amount of apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to inhibit the activity of URAT-1in blood. In some embodiments are provided methods of inhibiting URAT-1activity in plasma by contacting the plasma with an amount of apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to inhibit the activity of URAT-1in plasma. In some embodiments are provided methods of inhibiting URAT-1activity in an animal by contacting said animal with an amount of apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein sufficient to inhibit the activity of URAT-1in said animal. In some embodiments are provided methods of inhibitingURAT-1 activity in a mammal by contacting said mammal with an amount ofa polymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein sufficient to inhibit the activity of URAT-1in said mammal. In some embodiments are provided methods of inhibitingURAT-1 activity in a human by contacting said human with an amount of apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, sufficient to inhibit the activity of URAT-1in said human.

Pharmaceutical Compositions

Described herein are pharmaceutical compositions comprising an effectiveamount of a polymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein. In some embodiments, the pharmaceuticalcompositions comprise an effective amount of a polymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein, and at least one pharmaceutically acceptablecarrier. In some embodiments, the pharmaceutical compositions comprisean effective amount of polymorphic form 1, as described herein, and atleast one pharmaceutically acceptable carrier. In some embodiments, thepharmaceutical compositions comprise an effective amount of polymorphic,form 2, as described herein, and at least one pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutical compositionscomprise an effective amount of a combination of polymorphic form 1 andform 2, as described herein, and at least one pharmaceuticallyacceptable carrier. In some embodiments the pharmaceutical compositionsare for the treatment of disorders. In some embodiments thepharmaceutical compositions are for the treatment of disorders in amammal. In some embodiments the pharmaceutical compositions are for thetreatment of disorders in a human. In some embodiments thepharmaceutical compositions are for the treatment or prophylaxis ofdisorders of uric acid metabolism. In some embodiments thepharmaceutical compositions are for the treatment or prophylaxis ofhyperuricemia. In some embodiments the pharmaceutical compositions arefor the treatment or prophylaxis of gout.

Modes of Administration, Formulations and Dosage Forms

Described herein are pharmaceutical compositions comprising apolymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, as described herein. The compound, compound forms and compositionsdescribed herein are administered either alone, or in combination with,pharmaceutically acceptable carriers, excipients, or diluents in apharmaceutical composition, according to standard pharmaceuticalpractice. Administration is effected by any method that enables deliveryof the compounds to the site of action. These methods include, thoughare not limited to delivery via enteral routes (including oral, gastricor duodenal feeding tube, rectal suppository and rectal enema),parenteral routes (injection or infusion, including intraarterial,intracardiac, intradermal, intraduodenal, intramedullary, intramuscular,intraosseous, intraperitoneal, intrathecal, intravascular, intravenous,intravitreal, epidural and subcutaneous), inhalational, transdermal,transmucosal, sublingual, buccal and topical (including epicutaneous,dermal, enema, eye drops, ear drops, intranasal, vaginal)administration, although the most suitable route depends upon, forexample, the condition and disorder of the recipient. Those of skill inthe art will be familiar with administration techniques that can beemployed with the compounds, compound forms, compositions and methodsdescribed herein. By way of example only, the compounds, compound formsand compositions described herein are, in some embodiments, administeredlocally to the area in need of treatment, by for example, local infusionduring surgery, topical application such as creams or ointments,injection, catheter, or implant, said implant made for example, out of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. The administration is, in someembodiments, by direct injection at the site of a diseased tissue ororgan.

The pharmaceutical compositions described herein are, for example, in aform suitable for oral administration as a tablet, capsule, pill,powder, sustained release formulations, solution, suspension, forparenteral injection as a sterile solution, suspension or emulsion, fortopical administration as an ointment or cream or for rectaladministration as a suppository. The pharmaceutical composition is, insome embodiments, in unit dosage forms suitable for singleadministration of precise dosages. Pharmaceutical compositions include acompound or compound form as described herein as an active ingredient,and a conventional pharmaceutical carrier or excipient. In someembodiments these compositions include other or additional medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Pharmaceutical compositions are conveniently presented in unit dosageform. In some embodiments, they are prepared with a specific amount ofactive compound by any of the methods well known or apparent to thoseskilled in the pharmaceutical arts.

Doses

The amount of pharmaceutical compositions administered will firstly bedependent on the mammal being treated. In the instances wherepharmaceutical compositions are administered to a human subject, thedaily dosage will normally be determined by the prescribing physicianwith the dosage generally varying according to the age, sex, diet,weight, general health and response of the individual patient, theseverity of the patient's symptoms, the precise indication or conditionbeing treated, the severity of the indication or condition beingtreated, time of administration, route of administration, thedisposition of the composition, rate of excretion, drug combination, andthe discretion of the prescribing physician. Also, the route ofadministration vary depending on the condition and its severity. Thepharmaceutical composition is, in some embodiments, in unit dosage form.In such form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose. Determination of the properdosage for a particular situation is within the skill of the art. Forconvenience, in some embodiments, the total daily dosage is divided andadministered in portions during the day if desired. The amount andfrequency of administration will be regulated according to the judgmentof the attending clinician physician considering such factors asdescribed above. Thus the amount of pharmaceutical composition to beadministered is variable depending upon the circumstances.Administration occurs in an amount of between about 0.001 mg/kg of bodyweight to about 100 mg/kg of body weight per day (administered in singleor divided doses), or at least about 0.1 mg/kg of body weight per day. Aparticular therapeutic dosage includes, in some embodiments, from about0.01 mg to about 7000 mg of compound, or, from about 0.05 mg to about2500 mg. The quantity of active compound in a unit dose of preparationis, in some embodiments, varied or adjusted from about 0.1 mg to 1000mg, from about 1 mg to 300 mg, or 10 mg to 200 mg, according to theparticular application. In some instances the particular therapeuticdosage is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about600 mg, about 700 mg or about 800 mg. In some instances, dosage levelsbelow the lower limit of the aforesaid range are more than adequate,while in other cases still larger doses are employed without causing anyharmful side effect, e.g. by dividing such larger doses into severalsmall doses for administration throughout the day. In combinationalapplications in which the compound is not the sole therapy, it ispossible to administer lesser amounts of compound and still havetherapeutic or prophylactic effect.

Combination Therapies

The compounds and compound forms described herein are administered as asole therapy or in combination with another therapy or therapies.

By way of example only, if one of the side effects experienced by apatient upon receiving a compound or compound form as described hereinis hypertension, then it may be appropriate to administer ananti-hypertensive agent in combination with the compound. Or, by way ofexample only, the therapeutic effectiveness of a compound or compoundform as described herein may be enhanced by administration of anadjuvant (i.e., by itself the adjuvant may only have minimal therapeuticbenefit, but in combination with another therapeutic agent, the overalltherapeutic benefit to the patient is enhanced). Or, by way of exampleonly, the benefit experienced by a patient may be increased byadministering a compound or compound form as described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. Regardless of the disease, disorderor condition being treated, the overall benefit experienced by thepatient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

In the instances where the compounds or compound forms as describedherein are administered with other therapeutic agents, they need not beadministered in the same pharmaceutical composition as other therapeuticagents, and may, because of different physical and chemicalcharacteristics, be administered by a different route. For example, thecompound or compound form as described herein may be administered orallyto generate and maintain good blood levels thereof, while the othertherapeutic agent may be administered intravenously. The determinationof the mode of administration and the advisability of administration,where possible, in the same pharmaceutical composition, is well withinthe knowledge of the skilled clinician. The initial administration canbe made according to established protocols known in the art, and then,based upon the observed effects, the dosage, modes of administration andtimes of administration can be modified by the skilled clinician.

The compounds, compound forms and compositions described herein (andwhere appropriate other chemotherapeutic agent) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) sequentially or separately, depending uponthe nature of the disease, the condition of the patient, and the actualchoice of other chemotherapeutic agent to be administered. Forcombinational applications and uses, the compounds, compound forms andcompositions described herein and the chemotherapeutic agent need not beadministered simultaneously or essentially simultaneously. Thus, thecompounds, compound forms and compositions as described herein may beadministered first followed by the administration of thechemotherapeutic agent; or the chemotherapeutic agent may beadministered first followed by the administration of the compounds,compound forms and compositions as described herein. This alternateadministration may be repeated during a single treatment protocol. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient. For example, the chemotherapeutic agent may beadministered first, especially if it is a cytotoxic agent, and then thetreatment continued with the administration of the compounds, compoundforms and compositions as described herein followed, where determinedadvantageous, by the administration of the chemotherapeutic agent, andso on until the treatment protocol is complete. Thus, in accordance withexperience and knowledge, the practicing physician can modify eachadministration protocol for treatment according to the individualpatient's needs, as the treatment proceeds. The attending clinician, injudging whether treatment is effective at the dosage administered, willconsider the general well-being of the patient as well as more definitesigns such as relief of disease-related symptoms. Relief ofdisease-related symptoms such as pain, and improvement in overallcondition can also be used to help judge effectiveness of treatment.

Specific, non-limiting examples of possible combination therapiesinclude use of the compounds, compound forms and compositions describedherein with Febuxostat, Allopurinol, Probenecid, Sulfinpyrazone,Losartan, Fenofibrate, Benzbromarone or PNP-inhibitors (such as, but notlimited to Forodesine, BCX-1777 or BCX-4208). This list should not beconstrued to be closed, but should instead serve as an illustrativeexample common to the relevant therapeutic area at present. Moreover,combination regimens may include a variety of routes of administration,including but not limited to oral, intravenous, intraocular,subcutaneous, dermal, and inhaled topical.

Diseases

Described herein are methods of treating a disease or disorder in anindividual suffering from the disease or disorder comprisingadministering to said individual an effective amount of a polymorph formas described herein of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid.

Also described herein are methods of preventing a disease or disorder inan individual comprising administering to said individual an effectiveamount of a polymorph form as described herein of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid.

The invention extends to the use of the compounds, compound forms andcompositions described herein, in the manufacture of a medicament fortreating or preventing a disease or disorder.

In some embodiments, the disease or disorder is hyperuricemia. Incertain instances, hyperuricemia is characterized by higher than normalblood levels of uric acid, sustained over long periods of time. Incertain instances, increased blood urate levels may be due to enhanceduric acid production (˜10-20%) and/or reduced renal excretion (˜80-90%)of uric acid. In certain instances, causes of hyperuricemia may includeobesity/weight gain, excessive alcohol use, excessive dietary purineintake (foods such as shellfish, fish roe, scallops, peas lentils, beansand red meat, particularly offal—brains, kidneys, tripe, liver), certainmedications, including low-dose aspirin, diuretics, niacin,cyclosporine, pyrazinamide, ethambutol, some high blood pressure drugsand some cancer chemotherapeutics, immunosuppressive and cytotoxicagents, specific disease states, particularly those associated with ahigh cell turnover rate (such as malignancy, leukemia, lymphoma orpsoriasis), and also including high blood pressure, hemoglobin diseases,hemolytic anemia, sickle cell anemia, various nephropathies,myeloproliferative and lymphoproliferative diseases,hyperparathyroidism, renal disease, conditions associated with insulinresistance and diabetes mellitus, and in transplant recipients, andpossibly heart disease, inherited enzyme defects, abnormal kidneyfunction (e.g. increased ATP turn over, reduced glomerular uratefiltration) and exposure to lead (plumbism or “saturnine gout”).

In certain instances, hyperuricemia may be asymptomatic, though isassociated with the following conditions: gout, gouty arthritis, uricacid stones in the urinary tract (urolithiasis), deposits of uric acidin the soft tissue (tophi), deposits of uric acid in the kidneys (uricacid nephropathy), and impaired kidney function, possibly leading tochronic and acute renal failure.

In further or additional embodiments, the disease or disorder is gout,which is a condition that results from uric acid crystals depositing intissues of the body. It is often related to an inherited abnormality inthe body's ability to process uric acid, but may also be exacerbated bya purine rich diet. Defective uric acid processing may lead to elevatedlevels of uric acid in the blood causing recurring attacks of jointinflammation (arthritis), uric acid deposits in and around the joints,tophaceous gout, the formation of tophi, decreased kidney function, andkidney stones. Approximately 3-5 million people in the United Statessuffer from attacks of gout with attacks more prevalent in men than inwomen. In certain instances, gout is one of the most common forms ofarthritis, accounting for approximately 5% of all arthritis cases. Incertain instances, kidney failure and urolithiasis occur in 10-18% ofindividuals with gout and are common sources of morbidity and mortalityfrom the disease.

Gout is associated with hyperuricemia. In certain instances, individualssuffering from gout excrete approximately 40% less uric acid thannon-gouty individuals for any given plasma urate concentration. Incertain instances, urate levels increase until the saturation point isreached. In certain instances, precipitation of urate crystals occurswhen the saturation point is reached. In certain instances, thesehardened, crystallized deposits (tophi) form in the joints and skin,causing joint inflammation (arthritis). In certain instances, depositsare be made in the joint fluid (synovial fluid) and/or joint lining(synovial lining). Common areas for these deposits are the large toe,feet, ankles and hands (less common areas include the ears and eyes). Incertain instances, the skin around an affected joint becomes red andshiny with the affected area being tender and painful to touch. Incertain instances, gout attacks increase in frequency. In certaininstances, untreated acute gout attacks lead to permanent joint damageand disability. In certain instances, tissue deposition of urate leadsto: acute inflammatory arthritis, chronic arthritis, deposition of uratecrystals in renal parenchyma and urolithiasis. In certain instances, theincidence of gouty arthritis increases 5 fold in individuals with serumurate levels of 7 to 8.9 mg/dL and up to 50 fold in individuals withlevels>9 mg/dL (530 μmol/L). In certain instances, individuals with goutdevelop renal insufficiency and end stage renal disease (i.e., “goutynephropathy”). In certain instances, gouty nephropathy is characterizedby a chronic interstitial nephropathy, which is promoted by medullarydeposition of monosodium urate.

In certain instances, gout includes painful attacks of acute,monarticular, inflammatory arthritis, deposition of urate crystals injoints, deposition of urate crystals in renal parenchyma, urolithiasis(formation of calculus in the urinary tract), and nephrolithiasis(formation of kidney stones). In certain instances, secondary goutoccurs in individuals with cancer, particularly leukemia, and those withother blood diseases (e.g. polycythemia, myeloid metaplasia, etc).

In certain instances, attacks of gout develop very quickly, frequentlythe first attack occurring at night. In certain instances, symptomsinclude sudden, severe joint pain and extreme tenderness in the jointarea, joint swelling and shiny red or purple skin around the joint. Incertain instances, the attacks are infrequent lasting 5-10 days, with nosymptoms between episodes. In certain instances, attacks become morefrequent and last longer, especially if the disease is not controlled.In certain instances, episodes damage the affected joint(s) resulting instiffness, swelling, limited motion and/or persistent mild to moderatepain.

Plumbism or “saturnine gout,” is a lead-induced hyperuricemia thatresults from lead inhibition of tubular urate transport causingdecreased renal excretion of uric acid. In certain instances, more than50% of individuals suffering from lead nephropathy suffer from gout. Incertain instances, acute attacks of saturnine gout occur in the kneemore frequently than the big toe. In certain instances, renal disease ismore frequent and more severe in saturnine gout than in primary gout. Incertain instances, treatment consists of excluding the individual fromfurther exposure to lead, the use of chelating agents to remove lead,and control of acute gouty arthritis and hyperuricemia. In certaininstances, saturnine gout is characterized by less frequent attacks thanprimary gout. In certain instances, lead-associated gout occurs inpre-menopausal women, an uncommon occurrence in non lead-associatedgout.

In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's syndrome)affects about one in 100,000 live births. In certain instances, LNS iscaused by a genetic deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HGPRT). In certain instances, LNS is anX-linked recessive disease. In certain instances, LNS is present atbirth in baby boys. In certain instances, the disease leads to severegout, poor muscle control, and moderate mental retardation, which appearin the first year of life. In certain instances, the disease alsoresults in self-mutilating behaviors (e.g., lip and finger biting, headbanging) beginning in the second year of life. In certain instances, thedisease also results in gout-like swelling in the joints and severekidney problems. In certain instances, the disease leads neurologicalsymptoms include facial grimacing, involuntary writhing, and repetitivemovements of the arms and legs similar to those seen in Huntington'sdisease. The prognosis for individuals with LNS is poor. In certaininstances, the life expectancy of an untreated individual with LNS isless than about 5 years. In certain instances, the life expectancy of atreated individual with LNS is greater than about 40 years of age.

In certain instances, hyperuricemia is found in individuals withcardiovascular disease (CVD) and/or renal disease. In certain instances,hyperuricemia is found in individuals with prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome,endothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.In certain instances, hyperuricemia is found in individuals with obesity(e.g., central obesity), high blood pressure, hyperlipidemia, and/orimpaired fasting glucose. In certain instances, hyperuricemia is foundin individuals with metabolic syndrome. In certain instances, goutyarthritis is indicative of an increased risk of acute myocardialinfarction. In some embodiments, administration of a compound describedherein to an individual are useful for decreasing the likelihood of aclinical event associated with a disease or condition linked tohyperuricemia, including, but not limited to, prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome,endothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.

In some embodiments, a compound or compound form as described herein isadministered to an individual suffering from a disease or conditionrequiring treatment with a diuretic. In some embodiments, a compound orcompound form as described herein is administered to an individualsuffering from a disease or condition requiring treatment with adiuretic, wherein the diuretic causes renal retention of urate. In someembodiments, the disease or condition is congestive heart failure oressential hypertension.

In some embodiments, administration of a compound or compound form asdescribed herein to an individual is useful for improving motility orimproving quality of life.

In some embodiments, administration of a compound or compound form asdescribed herein to an individual is useful for treating or decreasingthe side effects of cancer treatment.

In some embodiments, administration of a compound or compound form asdescribed herein to an individual is useful for decreasing kidneytoxicity of cis-platin.

In certain instances, gout is treated by lowering the production of uricacid. In certain instances, gout is treated by increasing the excretionof uric acid. In certain instances, gout is treated by a URAT 1inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenaseinhibitor, a xanthine oxidoreductase inhibitor, a purine nucleosidephosphorylase (PNP) inhibitor, a uric acid transporter (URAT) inhibitor,a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solutecarrier family 2 (facilitated glucose transporter), member 9 (SLC2A9)inhibitor, an organic anion transporter (OAT) inhibitor, an OAT-4inhibitor, or combinations thereof. In general, the goals of gouttreatment are to i) reduce the pain, swelling and duration of an acuteattack, and ii) prevent future attacks and joint damage. In certaininstances, gout attacks are treated successfully using a combination oftreatments. In certain instances, gout is one of the most treatableforms of arthritis.

i) Treating the gout attack. In certain instances, the pain and swellingassociated with an acute attack of gout can be addressed withmedications such as acetaminophen, steroids, nonsteroidalanti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH) orcolchicine. In certain instances, proper medication controls gout within12 to 24 hours and treatment is stopped after a few days. In certaininstances, medication is used in conjunction with rest, increased fluidintake, ice-packs, elevation and/or protection of the affected area/s.In certain instances, the aforementioned treatments do not preventrecurrent attacks and they do not affect the underlying diseases ofabnormal uric acid metabolism.

ii) Preventing future attacks. In certain instances, reducing serum uricacid levels below the saturation level is the goal for preventingfurther gout attacks. In some cases, this is achieved by decreasing uricacid production (e.g. allopurinol), or increasing uric acid excretionwith uricosuric agents (e.g. probenecid, sulfinpyrazone, benzbromarone).

In certain instances, allopurinol inhibits uric acid formation,resulting in a reduction in both the serum and urinary uric acid levelsand becomes fully effective after 2 to 3 months.

In certain instances, allopurinol is a structural analogue ofhypoxanthine, (differing only in the transposition of the carbon andnitrogen atoms at positions 7 and 8), which inhibits the action ofxanthine oxidase, the enzyme responsible for the conversion ofhypoxanthine to xanthine, and xanthine to uric acid. In certaininstances, it is metabolized to the corresponding xanthine analogue,alloxanthine (oxypurinol), which is also an inhibitor of xanthineoxidase. In certain instances, alloxanthine, though more potent ininhibiting xanthine oxidase, is less pharmaceutically acceptable due tolow oral bioavailability. In certain instances, fatal reactions due tohypersensitivity, bone marrow suppression, hepatitis, and vasculitishave been reported with Allopurinol. In certain instances, the incidenceof side effects may total 20% of all individuals treated with the drug.Treatment for diseases of uric acid metabolism has not evolvedsignificantly in the following two decades since the introduction ofallopurinol.

In certain instances, uricosuric agents (e.g., probenecid,sulfinpyrazone, and benzbromarone) increase uric acid excretion. Incertain instances, probenecid causes an increase in uric acid secretionby the renal tubules and, when used chronically, mobilizes body storesof urate. In certain instances, 25-50% of individuals treated withprobenecid fail to achieve reduction of serum uric acid levels<6 mg/dL.In certain instances, insensitivity to probenecid results from drugintolerance, concomitant salicylate ingestion, and renal impairment. Incertain instances, one-third of the individuals develop intolerance toprobenecid. In certain instances, administration of uricosuric agentsalso results in urinary calculus, gastrointestinal obstruction, jaundiceand anemia.

Successful treatment aims to reduce both the pain associated with acutegout flare and long-term damage to the affected joints Therapeutic goalsinclude providing rapid and safe pain relief, preventing furtherattacks, preventing the formation of tophi and subsequent arthritis, andavoiding exacerbating other medical conditions. Initiation of treatmentdepends upon the underlying causes of hyperuricemia, such as renalfunction, diet, and medications. While gout is a treatable condition,there are limited treatments available for managing acute and chronicgout and a number of adverse effects are associated with currenttherapies. Medication treatment of gout includes pain management,prevention or decrease in joint inflammation during an acute goutyattack, and chronic long-term therapy to maintain decreased serum uricacid levels.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effectiveanti-inflammatory medications for acute gout but are frequentlyassociated with irritation of the gastrointestinal (GI) system,ulceration of the stomach and intestines, and occasionally intestinalbleeding. Colchicine for acute gout is most commonly administered orallyas tablets (every 1-2 hours until there is significant improvement inpain or the patient develops GI side effects such as severe diarrhea,nausea and vomiting), or intravenously. Corticosteroids, given in shortcourses, can be administered orally or injected directly into theinflamed joint.

Medications are available for reducing blood uric acid levels thateither increase renal excretion of uric acid by inhibiting re-uptake orreduce production of uric acid by blockade of xanthine oxidase. Thesemedicines are generally not initiated unfit after the inflammation fromacute gouty arthritis has subsided because they may intensify theattack. If they are already being taken prior to the attack, they arecontinued and only adjusted after the attack has resolved. Since manysubjects with elevated blood uric acid levels may not develop goutyattacks or kidney stones, the decision for prolonged treatment with uricacid-lowering medications is individualized.

Kits

The compounds, compound forms, compositions and methods described hereinprovide kits for the treatment of diseases and disorders, such as theones described herein. These kits comprise a compound, compound form,compounds, compound forms or compositions described herein in acontainer and, optionally, instructions teaching the use of the kitaccording to the various methods and approaches described herein. Suchkits, in some embodiments, also include information, such as scientificliterature references, package insert materials, clinical trial results,and/or summaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. Kits described herein are provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits are also, in some embodiments,marketed directly to the consumer.

Provided in certain embodiments, are compositions or kits comprising2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(e.g., a polymorph thereof, such as Form 1), a double low densitypolyethylene plastic bag, and an HDPE container. In further embodiments,the composition or kit further comprises a foil bag (e.g., an anhydrousfoil bag, such as a heat sealed anhydrous foil bag). In someembodiments, the composition or kit further comprises a desiccant; instill other embodiments, a desiccant is not necessary and/or present. Insome instances, such packing improves the stability of the2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(e.g., Form 1).

In some embodiments, the compounds, compound forms and pharmaceuticalcompositions described herein are utilized for diagnostics and asresearch reagents. For example, in some embodiments, the compounds,compound forms and pharmaceutical compositions, either alone or incombination with other compounds, are used as tools in differentialand/or combinatorial analyses to elucidate expression patterns of genesexpressed within cells and tissues. As one non-limiting example,expression patterns within cells or tissues treated with one or morecompounds are compared to control cells or tissues not treated withcompounds and the patterns produced are analyzed for differential levelsof gene expression as they pertain, for example, to disease association,signaling pathway, cellular localization, expression level, size,structure or function of the genes examined. These analyses areperformed on stimulated or unstimulated cells and in the presence orabsence of other compounds which affect expression patterns.

Besides being useful for human treatment, the compounds, compound formsand pharmaceutical compositions described herein are also useful forveterinary treatment of animals.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations.

EXAMPLES I. Preparation of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid Example 1A Preparation of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid via methyl2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateintermediate

2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid was prepared according to previously described procedures (see USpatent application publication US 2009/0197825) as outlined in thescheme below.

Example 1B Preparation of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl-4H-1,2,4-triazol-3-ylthio)aceticacid via2-(4-(4-cyclopropylnaphthalen-1-yl)-5-hydroxy-4H-1,2,4-triazol-3-ylthio)aceticacid intermediate

Preparation of 1-cyclopropyl-4-isothiocyanatonaphthalene has beenpreviously described (see US patent application publication US2009/0197825). In brief, 1-bromonaphthalene is coupled withcyclopropylmagnesium bromide to form 1-cyclopropylnaphthalene. Reactionwith sodium nitrite forms the nitro derivative which is reduced bytreatment with hydrogen over Pd/C to form1-amino-4-cyclopropylnaphthalene. Finally, reaction with thiophosgeneprovides 1-cyclopropyl-4-isothiocyanatonaphthalene.

1-Cyclopropyl-4-isothiocyanatonaphthalene is reacted with hydrazine andthen cyclized in the presence of dimethyl carbonate to form4-(4-cyclopropylnaphthalen-1-yl)-5-mercapto-4H-1,2,4-triazol-3-ol.

Coupling of4-(4-cyclopropylnaphthalen-1-yl)-5-mercapto-4H-1,2,4-triazol-3-ol with2-chloroacetic acid provides2-(4-(4-cyclopropylnaphthalen-1-yl)-5-hydroxy-4H-1,2,4-triazol-3-ylthio)aceticacid.

Bromination of2-(4-(4-cyclopropylnaphthalen-1-yl)-5-hydroxy-4H-1,2,4-triazol-3-ylthio)aceticacid, utilizing protecting groups as required (such as protecting theacid as the i-propyl ester), provides2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid.

Example 1C Preparation of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatefrom methyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Aqueous sodium hydroxide solution (1N, 3.0 L, 3.0 mol, 1.25 eq) wasadded to a cooled (15-18° C.) mixture of methyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate-form2 (1.0 kg, 2.39 mol, 1 eq) and ethanol (9 L), at a rate to maintain aninternal temperature<25° C.: The mixture was then stirred at 20-25° C.(maintaining pH>12), while monitoring by HPLC and considered completewhen the sum of methyl and ethyl esters<0.5%, (˜3 hours). The mixturewas filtered through a medium frit funnel (10-16 micron) and thefiltrate concentrated in vacuo (40° C.) to a final volume of 5.2 L.Water (0.6 L) was added and the solution cooled to 0-5° C. withstirring. The resulting slurry was warmed (17-18° C.) over 1 h, thencooled (0-5° C.) over 2-3 h, and held at 0-5° C. for an additional 6-9h. The slurry was then filtered through a jacketed filter funnel (0-5°C.) lined with filter paper (3 micron) or filter cloth. The resultingcake was washed with pre-chilled (3-5° C.) water (3×1.25 L), allowed tode-liquor on the funnel (at least 3 h), and further dried in a vacuumoven (18-25° C., nitrogen sweep) until water content<13% w/w (˜0.8days). Sodium2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatewas isolated as a light yellow solid (696.4 g; KF=13%).

II. Preparation of Crystalline Polymorph Forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid Example 2 Preparation of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 1

2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 1 is prepared from crude sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateas described below:

Step 1: Sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(60 g) and water (300 mL) were stirred and briefly heated (40-50° C.)until all solids dissolved. The solution was cooled and stirred in anice bath for 1-2 hrs, after which time crystals began to form (or ifcrystallization had not begun, the solution was seeded with a smallamount of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatecrystals). Stirring in the ice bath was continued until crystallizationwas complete, and then the solid isolated by filtration through asintered filter funnel (medium porosity) under vacuum. The filter cakewas washed with ice-cold water (sufficient to cover the filter cake) andthe liquid completely drained under vacuum to provide wet filter cake(126.5 g).

Step 2: The filter cake was dissolved in water (˜70 g present in thefilter cake plus 130 mL; concentration 200-250 mg/mL) at 60-70° C., andslowly added to acetic acid (200 mL). The acetic acid/water (1:1 v/v)solution was cooled to room temperature under continuous stirring, andthen further cooled to 0° C., resulting in the formation of crystalswhich were isolated by vacuum filtration over a medium porosity sinteredfilter funnel. The solids were washed with ice-cold acid/water (1:1 v/v)and dried in a vacuum oven to provide2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (39.5 g, 78%).

Example 3 Preparation of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 2

2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 2 is prepared from sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateas described below:

A suspension of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(50.0 g of crude sample 97.6% a/a; KF=12.6%; 43.3 g calculated actual)and deionized water (217 mL) was heated (30-35° C.) with vigorousstirring for 10-15 min, during which time the slurry dissolved leavingonly trace solids. The mixture was filtered through a medium-frit filterfunnel and the clear filtrate cooled to 10° C. Approximately one half ofa mixture of aqueous hydrogen bromide solution (48 wt %, 18 g, 106.8mmol, 1.05 eq) and deionized water (˜13 mL) was added to the filtrateover 10 min, at 10-15° C., during which time some solids were formed.Ethyl acetate (347 mL) was added with vigorous stirring resulting indissolution of all solids. The remaining hydrogen bromide solution wasadded over 10 min at 10° C., and stirring continued for 5-10 min, duringwhich time a cloudy suspension formed. Stirring was stopped, the phasesallowed to separate and the aqueous layer removed. The organic layer waswashed with deionized water (110 mL) with vigorous stirring for 5-10min, and after phase separation the aqueous layer removed. The organiclayer was heated to 45-50° C. and solvents removed using gentle vacuum,resulting in the formation of a slurry (final volume ˜200 mL), which waswarmed (45-50° C.) with moderate stirring for 1 h, gradually (3-4 h)cooled to 20-25° C., and held at 20-25° C. for an additional 12 h, andfinally cooled to 5-10° C. and held for 20-30 min. The slurry was thenfiltered under vacuum through a Buchner funnel lined with Whatman No. 3filter paper. There were fast filtering solids and the mother liquor wascycled through the vessel to recover residual solids which werecollected with the initial batch. The solids were washed with cold (5°C.) ethyl acetate (26 mL) and allowed to dry on the funnel for at least10 min, then soaked in n-heptane (30 mL) for at least 10 min and thevacuum reapplied for ˜6 h. The solids were transferred to a drying dishand dried in a vacuum oven (25 mmHg) for at least 16 h at 35-40° C.,with nitrogen sweep.2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 2 was obtained as a free flowing off-white solid (28.39 g,69%), containing trace amounts of water (0.16 wt %) and ethyl acetate(700 ppm).

Materials Amount Sodium 2-(5-bromo-4-(4-cyclopropyl naphthalen- 50.0 gcrude 1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (43.3 g corrected)Hydrogen bromide (48 wt %) 18.0 g Water 217 mL Ethyl acetate 346.7 mLWater (wash 1) 108.3 mL Water (wash 2) 108.3 mL Ethyl acetate (wash) 26mL n-Heptane (wash) 30 mL

Example 4 Conversion of2-(5-bromo-4-(4-cyclopropylnaphthalen-triazol-3-ylthio)aceticAcid-Polymorph form 1 to Polymorph Form 2

Method 1

Ethyl acetate (200 mL) was added to a solution of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-polymorph form 1 (30 g) in acetone (200 mL) at 60° C. A portion ofthe solvent (˜200 mL) was removed under low vacuum and fresh ethylacetate (200 mL) was added, followed by another distillation cycle,during which crystallization began. The temperature of the water bathwas slowly increased to 70° C., during which time four additional ethylacetate addition/distillation cycles were carried out to a final volumeof ˜200 mL. The mixture was allowed to cool slowly to room temperatureand then placed in the fridge overnight. Solids were isolated byfiltration, washed with ice-cold ethyl acetate and dried in a vacuumoven to provide of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 2.

Method 2

A solution of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid-form 1 in one of the solvents listed below was slowly evaporated atroom temperature to crystallize, refrigerated, the solid crystalsisolated and washed with solvent to produce Solid Polymorph form 2,containing trace amounts of solvent and water, as indicated.

Solvent Water Polymorph Solvent content (%) content (%) Purity FormButan-2-one 0.35 0.36 2 0.49 0.53 tert-Butanol 0.32 0.17 94% 2 0.72 0.5 4% impurities Dichloromethane 0.3 0.5 2

Method 3

Solid Polymorph form 1 was held in equilibrium with its saturatedacetonitrile, ethyl, acetate or toluene solution at 60° C. for 6 days toproduce Solid Polymorph form 2.

Solid Polymorph form 1 held in equilibrium with its saturated acetonesolution at 60° C. for 6 days resulted in decomposition.

Method 4

Solid Polymorph form 1 and solvent (20 μL) were heated at 60° C. for 13days to produce Solid Polymorph form 2.

form 1 (mg) Solvent Polymorph Form Isolated 928 DMF 2 927 Dioxane 2 883Acetic acid 2 844 Toluene 2 844 Acetonitrile/toluene 2 (20 μL each) 844Acetonitrile 1 & 2 867 iso-Propanol 1 & 2 944 Water 1

III. Analysis of Crystalline Polymorph Forms of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid Example 5A Analysis of Crystalline Polymorph Form 1 X-Ray PowderDiffraction

The X-ray powder diffraction pattern of polymorph form 1 is shown inFIGS. 1 (raw data) and 2 (background subtracted and Kα2 stripped);observed and representative peaks in the XRPD pattern are shown in thetables below (generated on background corrected and Kα2 stripped file).

form 1 Observed °2θ d space (Å) Intensity (%) 10.32 8.562 100 18.844.706 32.7 20.75 4.277 23.2 27.28 3.266 13.6 27.60 3.229 11 21.54 4.12310.4 25.53 3.487 9.8 6.80 12.989 9.4 24.97 3.563 9.1 28.43 3.137 8.419.98 4.441 6.9 29.35 3.040 6.7 15.88 5.577 5.4 23.13 3.842 4.8 26.343.381 4.8 18.56 4.777 4.1

form 1 Representative °2θ d space (Å) Intensity (%) 10.32 8.562 10018.84 4.706 32.7 20.75 4.277 23.2 27.28 3.266 13.6

Differential Scanning Calorimetry (DSC)

The differential scanning calorimetry trace for form 1 is shown in FIG.3; a transition temperature of 150.7° C. was recorded.

Scanning Electron Microscopy (SEM)

SEM analysis showed form 1 primary crystals are composed of agglomerates(typical size ˜25 μm) of plate-like crystals (size ˜5 μm).

Thermogravimetric Analysis (TGA)

Replicate TGA scans for form 1 are shown in FIGS. 4 (a) and (b),indicating the material does not contain significant levels of volatiles

Solubility

Form 1 (˜25 mg) and acetate buffer (25 mM, pH 5, 4 mL), prepared withand without sodium chloride (ionic strength adjusted to =0.1M), wereplaced in a glass vial which was sealed and placed on a laboratoryrotator in a 25° C. incubator. After 1, 5, and 7 days the samples werefiltered and assayed by HPLC. Form 1 solubility (mg/mL), at the varioustime points, with and without sodium chloride, is shown in the tablebelow:

Day 1 Day 5 Day 7 No NaCl 0.2652 (pH 4.95) 0.2134 (pH 4.85) 0.1569 (pH4.75) NaCl (I = 0.1) 0.2995 0.2566 (pH 4.79) 0.3045 (pH 4.81)

Example 5B Analysis of Crystalline Polymorph Form 2 X-Ray PowderDiffraction

The X-ray powder diffraction pattern of polymorph form 2 is shown inFIGS. 5 (raw data) and 6 (background subtracted and Kα2 stripped);observed and representative peaks in the XRPD pattern are shown in thetables below (generated on background corrected and Kα2 stripped file).

form 2 Observed °2θ d space (Å) Intensity (%) 7.97 11.086 13.8 9.669.148 26.1 10.46 8.449 83.8 11.96 7.394 41.3 12.55 7.046 16.7 12.946.836 15.7 13.82 6.402 41.6 16.19 5.471 49.8 18.21 4.867 74.0 18.764.727 81.4 19.02 4.662 35.6 19.51 4.548 15.9 19.83 4.474 100.0 20.404.349 13.4 21.36 4.157 12.3 22.50 3.948 36.7 22.88 3.884 30.6 23.083.850 56.1 24.01 3.704 42.1 25.15 3.539 35.2 25.46 3.496 20.5 26.063.417 13.4 26.51 3.360 35.7 27.97 3.187 26.8 29.93 2.983 37.0 30.422.936 12.4 31.77 2.814 17.1 32.35 2.765 38.2 34.26 2.615 12.8 38.012.366 16.5 38.88 2.314 10.0

form 2 Representative °2θ d space (Å) Intensity (%) 19.83 4.474 100.010.46 8.449 83.8 18.76 4.727 81.4 18.21 4.867 74.0 23.08 3.850 56.1

FIG. 7, shows an overlay of the XRPD Patterns (y-axis offset) of form 1(lower) and form 2 (upper).

Differential Scanning Calorimetry (DSC)

The differential scanning calorimetry trace for form 2 is shown in FIG.8, a melting point at 174.7° C. was recorded.

¹H NMR Spectroscopy

The ¹H NMR spectrum, taken in DMSO-d₆, of polymorph form 2 is shown inFIG. 9 and the major peaks listed in the table below:

ppm peak integration 12.96 s 1.00 8.58 d 1.01 7.74 td 1.01 7.65 m 2.027.44 d 1.01 7.16 d 1.00 3.99 d 2.02 2.49-2.58 m 1.00 1.16 m 2.03 0.88 d2.01

HPLC

The HPLC trace of polymorph form 2 is shown in FIG. 10. The peak listingfor the trace is given in the table below:

Peak Ret time Width Area # (min) Type (min) (mAU * s) Area (%) 1 6.111BB 0.0621 5.24158 0.0438 2 11.514 VB 0.1157 39.57644 0.3311 3 13.741 BB0.1436 2.56681 0.0215 4 143676 BB 0.1463 3.02621 0.0253 5 17.694 BB0.1785 3.37245 0.0282 6 18.791 BB 0.2269 11,881.6 99.3931 7 19.891 BB0.2502 5.15241 0.0431 8 32.169 BB 0.1785 8.54182 0.0715 9 41.636 BB0.1163 5.06670 0.0424

Scanning Electron Microscopy (SEM)

SEM analysis showed form 2 primary crystals are composed of agglomerates(typical size ˜25 μm) of column-like crystals (size ˜10 μm).

Thermogravimetric Analysis (TGA)

Overlay of TGA scans for form 2 are shown in FIG. 11, indicating thematerial does not contain significant levels of volatiles.

Solubility

Form 2 (˜25 mg) and acetate buffer (25 mM, pH 5, 4 mL), prepared withand without sodium chloride (ionic strength adjusted to =0.1M), wereplaced in a glass vial which was sealed and placed on a laboratoryrotator in a 25° C. incubator. After 1, 5, and 7 days the samples werefiltered and assayed by HPLC. Form 2 solubility (mg/mL), at the varioustime points, with and without sodium chloride, is shown in the tablebelow:

Day 1 Day 5 Day 7 No NaCl 0.1867 (pH 4.91) 0.1957 (pH 4.73) 0.1337 (pH4.79) NaCl (I = 0.1) 0.2192 0.2441 (pH 4.83) 0.2157 (pH 4.85)

Form 2 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatewas tested under various conditions to determine drug substancestability. No degradation of packaged Form 2 was observed for 1 monthunder accelerated conditions (40° C.-75% RH, or 25° C.-60% RH).Packaging was in a double low density polyethylene plastic bags inside aHDPE container.

Stability of crystalline polymorph2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

The crystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatewere found to exhibit increased stability in comparison to the amorphoussolid state form of the carboxylic acid. The improved stability of thecrystalline polymorphs of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateprovides for the preparation of pharmaceutical dosage forms displayingreduced variability in the dosage present in a given dosage form,reduction in the presence of impurities in the final pharmaceuticalproduct, and an improved shelf life of formulated dosage forms whencompared to the pharmaceutical dosage form prepared with the amorphoussolid state form of the carboxylic acid.

IV Analytical techniques Example 6A X-Ray Powder Diffraction (XRPD)

XRPD patterns were collected on a Bruker D8 Advance diffractometer inthe Bragg-Brentano theta/theta configuration. An incident x-ray beam wasproduced using a CuKα (λ=1.5418A) anode (tube voltage=40 kV, current=40mA), made parallel with a 1.0 mm primary Soller slit on the source sideand 1.0 mm secondary Soller slit on the detector side. CuKβ radiationwas removed with a graphite monochromator slit of 1.0 mm on the detectorside. A scintillation detector (Nal) was used with slit of 0.1 mm. Acontinuous scan of 0.02°2θ step size and 5 s per step from 2-50°2θ wasused. Approximately 25 mg of material was carefully pressed onto a Sizero background wafer to ensure a flat preparation. Data were collectedusing Bruker Diffrac^(plus) XRD Commander v2.3 software. Peak lists weregenerated using Bruker Diffrac^(Plus) EVA v9.0 software with backgroundsubtraction and Kat stripping. The instrument alignment check was donewith a NIST alumina standard SRM1976. XRPD (Bruker D8 Advance)instrument conditions are summarized in the table below:

Instrument Parameter Setting Configuration Bragg-Brentano Theta/thetaDetector Type Scintillation (NaI) Source Type CuKα = 1.5418 Å SourcePrimary Soller Slit 1.0 mm Detector Secondary Soller Slit 1.0 mmDetector Slit 0.1 mm Monochromator (graphite) Slit 1.0 mm Scan Range 2to 50 °2θ Step Size 0.02 °2θ Time per Step 5 sec

Example 6B Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry was performed using a TA InstrumentsQ2000 differential scanning calorimeter. Temperature calibration wasperformed using NIST traceable indium metal. Duplicate samples wereprepared by sealing approximately 2-5 mg (accurately recorded) ofmaterial into a TA Tzero non-hermetic pan. A Tzero non-hermetic pan/lidwas weighed and used on the reference side of the cell. Samples wereheated at a rate of 10° C./min from 25° C. to 200° C., using a 50 mL/minnitrogen purge gas flow rate. The melting temperature (T_(m)) and theheat of melting (ΔH_(m)) were measured using TA Universal Analysissoftware v4.4.

Example 6C Scanning Electron Microscopy (SEM)

SEM images were collected on a JEOL SEM model JSM-6100. The sample wassprinkled onto an SEM stub containing double-sided carbon tape and wassputter coated with gold for 60 s using the Denton Desk II unit. The SEMwas operated at 15 kV accelerating voltage. Images were collected usingsoftware DIPS v2.5 (Digital Imaging Processing System) with the slowscan set to 800×640 pixels and integrator at 50 μs with no averaging.Images were collected at magnification ranging from 50× to 5000×.

Example 6D Thermogravimetric Analysis (TGA

Thermogravimetric analysis (TGA) was performed using a TA InstrumentQ5000. Weight calibration was checked using a certified 50 mg weight.Duplicate samples were prepared by weighing ˜5-10 mg material into a TAPt pan. Samples were heated at a rate of 10° C./min to 200° C., using a25 mL/min nitrogen purge gas flow rate. Weight losses were measuredusing TA Universal Analysis software v4.4.

1. A crystalline polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid:

characterized by peaks at 10.32, 18.84 and 20.75°2θ±0.1° 2θ. 2.-3.(canceled)
 4. The crystalline polymorph form 1 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid. 5.-8. (canceled)
 9. A crystalline polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid:

characterized by peaks at 10.46, 18.76, and 19.83 °2θ+0.1° 2θ.
 10. Thecrystalline polymorph of claim 9, further characterized by at least onefurther peak at 18.21 or 23.08°2θ±0.1° 2θ.
 11. The crystalline polymorphof claim 9 that exhibits an x-ray powder diffraction patternsubstantially the same as the x-ray powder diffraction pattern shown inFIG.
 5. 12. The crystalline polymorph form 2 of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid.
 13. A crystalline polymorphic form of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid prepared by a method comprising the step of crystallizing2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid from a mixture of water and ethyl acetate.
 14. A solidpharmaceutical composition comprising: an effective amount of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, the2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid comprising the crystalline polymorph of claim 12 as an activeingredient; and at least one excipient or carrier.
 15. A method fortreating or preventing hyperuricemia, or a disease caused by elevateduric acid levels, comprising administering an effective amount of thecrystalline polymorph of claim
 12. 16. A method for treating orpreventing gout comprising administering an effective amount of thecrystalline polymorph of claim
 12. 17. (canceled)
 18. A process for thepreparation of a crystalline polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4,-triazol-3-ylthio)aceticacid, the process comprising: dissolving sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatein water resulting in a solution; adding a mineral acid (e.g., about 1equivalent); adding ethylacetate; separating an organic layer;precipitating the crystalline polymorph from the organic layer (e.g., bycooling and/or reducing the volume of the organic layer); wherein thecrystalline polymorph is characterized by peaks at 10.46, 18.76, and19.83°2θ±0.1° 2θ.
 19. The process of claim 18, wherein the process incharacterized by one or more of the following: the mineral acidcomprises hydrobromic acid; the mineral acid is added at about 1.05equivalents; the volume of the organic layer is reduced to precipitatethe crystalline polymorph; the organic layer is cooled to precipitatethe crystalline polymorph; the crystalline polymorph is filtered andwashed; and/or the crystalline polymorph is further characterized by atleast one further peak at 18.21 or 23.08°2θ±0.1°20.
 20. A process forthe preparation of a crystalline polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4,-triazol-3-ylthio)aceticacid, comprising: (a) contacting sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatewith aqueous hydrogen bromide solution and an organic solvent to form anaqueous phase and an organic phase; (b) isolating the organic phase fromthe mixture of step (a); and (c) crystallizing2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid from the organic phase.
 21. A process for the preparation of acrystalline polymorph of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4,-triazol-3-ylthio)aceticacid, comprising crystallizing 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid from a mixture ofwater and ethyl acetate.
 22. A solid pharmaceutical compositioncomprising:2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4,-triazol-3-ylthio)aceticacid form 1 as an active ingredient; and2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4,-triazol-3-ylthio)aceticacid form 2 as an active ingredient; and at least one excipient orcarrier.